Case 2 -
Well differentiated (WHO Grade II) Astrocytoma
Peter C. Burger
Johns Hopkins Hospital
Click on each slide thumbnail image for an enlarged view
A 37-year-old-woman was evaluated two days after a seizure. A large, intra-axial, non-enhancing mass
was found in the left frontal lobe.
Diagnosis - Well differentiated (WHO Grade II) Astrocytoma
Case 2 - Figure 1 - Astrocytoma. Note somewhat elongated, oval and mildly pleomorphic nuclei in this cytologic preparation. (A) A large, expansile, intra-axial left frontal lobe mass is present in a T2-weighted MR image.
Case 2 - Figure 2 - Astrocytoma. Characteristic of the fibrillary astrocytomas are a patternless infiltrate, nuclear pleomorphism with angulated and oval contours, and eosinophilic cytoplasmic processes. (B) The lesion does not enhance (T1-weighted, post contrast image).
Case 2 - Figure 3 - Astrocytoma. Many diffuse fibrillary astrocytomas exhibit nuclear immunolabeling for p53. Widespread labeling of this sort is encountered in only a small minority of oligodendrogliomas. (C) Photomicrograph.
The histologic section is clearly that of an infiltrating glioma; type and the grade are the issues.
Neuropathologists evaluating infiltrating gliomas such as this today take one or two tacts. The vast
majority of microscopists assume the lesion is oligodendroglioma, or at least mixed glioma
(oligoastrocytoma), until proven otherwise. This approach has of course, created a virtual "epidemic" of
this entity, driven by the desire of the patient (for a more favorable diagnosis relative to infiltrating
astrocytoma), the clinician (who can treat these lesions more effectively than astrocytomas), and the
pathologist (who makes everyone happy with the diagnosis of oligodendroglioma and in desperation can
always cover both bases with a diagnosis of "mixed glioma").1
The diagnostic criteria for oligodendroglioma have thus loosened considerably since the original
description of oligodendroglioma in the 1920's. It is my recommendation these diagnostic criteria be
tightened, returning essentially to original criteria. By this approach, we assume this lesion is
astrocytic until proven oligodendroglial.
Oligodendroglioma is known largely for its monotony in nuclear size and shape. In all but the higher
grade lesions, the nuclei are almost uniformly round and often contain a small, but prominent,
nucleolus. Nuclei of astrocytomas, in contrast, although they may be round focally are noted for more
variation in size, shape, and polarity. They are individually often denser and without prominent
nucleoli. It is this emphasis on nuclear features that harks back to original cytological/histological
The monotony of oligodendrogliomas also extends to the cell density, such that large areas are
strikingly uniform and uniformly blue. Nuclei with an astrocytoma, in addition to being pleomorphic, are
also unevenly distributed. Other distinctive features of the oligodendroglioma are well circumscribed
nodules of increased cellularity that are only rarely seen in astrocytomas. Perinuclear haloes are a
classic signature feature of oligodendrogliomas but are actually a "soft" finding in the absence of the
monotony described above. Such cytoplasmic clearing can be prominent in astrocytomas. Another helpful
feature of oligodendrogliomas, particularly when higher in grade, is extensive cortical infiltration with
a subpial concentration and perineuronal satellitosis. Similar cortical invasion can be noted in some
highly infiltrative astrocytic tumors, however.
Fortunately, a molecular/cytogenetic profile has emerged that appears to aid in the distinction
between oligodendroglioma and astrocytoma, or at least in identifying "oligodendrogliomas" that are
biologically indolent or more responsive to treatment. This genetic profile is combined loss of
chromosomal arms 1p and 19q, as detected clinically either by fluorescent in situ hybridization or
PCR-based approaches that evaluate loss of heterozygosity.2, 3, 6, 7 Multiple studies have confirmed
the high incidence of this genetic loss when strict histologic criteria are used for the diagnosis of
oligodendroglioma, but a considerably lower concordance, in some cases as poor as 30%, when "loose"
histological criteria are employed.6,7
An unresolved issue is the appropriate diagnosis for "oligodendrogliomas" without this loss. To some,
the histologic diagnosis has precedence, although in my opinion most of these lesions without 1p/19q loss
are astrocytomas, particularly if a tumor has genetic changes, e.g. gain of chromosome 7 or p53 mutations
(often associated with diffuse strongly positive nuclear staining by immunohistochemistry). Low grade,
"genetically proven" oligodendrogliomas rarely have p53 mutations.
There are, however, occasional cases that have classic oligodendroglial histopathological features yet
lack the chromosomal signature loss. I defer to the histologic diagnosis in this situation. Conversely,
there are rare "astrocytomas" with 1p/19q loss. These are often considered oligodendrogliomas.
The issue of mixed glioma is entirely unresolved, which should not be surprising given the difficulty
of defining the lesion. While it is diagnostically attractive, although molecularly unlikely, that mixed
lesions that have distinct areas with differing genetic changes reflecting oligodendroglial and
astrocytic lineages, this is yet to be demonstrated. Missing are the requisite microdissection studies.
Mixed gliomas appear to have no changes, those associated with astrocytomas, or those combined 1p/19q
loss associated with oligodendrogliomas.5
The issue of higher grade lesions and 1p loss is unresolved. One school suggests that loss of 1p
create some more favorable prognosis,4 but there is no unanimity on this issue. It is not our
practice to do molecular testing on grade IV lesions.
- Burger, P.C.: What is an Oligodendroglioma? Brain Pathol. 2002;12:257-259.
- Burger, P.C., Minn, A.Y., Smith, J.S., Borell, T.J., Jedlicka, A.E., Huntley, B.K., Goldthwaite,
P.T., Jenkins, R.B., and Feuerstein, B.G.: Losses of Chromosomal Arms 1p and 19q in the Diagnosis of
Oligodendroglioma. A Study of Paraffin-Embedded Sections. Mod. Pathol. 2001;14:842-853.
- Cairncross, J.G., Ueki, K., Zlatescu, M.C., Lisle, D.K., Finkelstein, D.M., Hammond, R.R., et. el.:
Specific Genetic Predictors of Chemotherapeutic Response and Survival in Patients with Anaplastic
Oligodendrogliomas. J. Natl. Cancer Inst. 1998;90:1473-1479.
- Ino, Y., Zlatescu, M.C., Sasaki, H., MacDonald, D.R., Stemmer-Rachamimov, A.O., Jhung, S., Ramsey,
D.A., von Deimling, A., Louis, D.N., and Cairncross, J.G.: Long Survival and Therapeutic Responses in
Patients with Histologically Disparate High-Grade Gliomas Demonstrating Chromosome 1p Loss. J.
- Maintz, D., Fiedler, K., Koopmann, J., Rollbrocker, B., Nechev, S., Lenartz, D., Stangl, A.P., Louis,
D.N., Schramm, J., Wiestler, O.D., and vonDiemling, A.: Molecular Genetic Evidence for Subtypes of
Oligoastrocytomas. J. Neuropathol. And Exper. Neurol. 1997;56:1098-1104.
- Sasaki, H., Zlatescu, M.C., Betensky, R.A., Johnk, L.B., Cutone, A.N., Cairncross, J.G., and Louis,
D.N.: Histopathological-Molecular Genetic Correlations in Referral Pathologist-Diagnosed Low-Grade
"Oligodendroglioma." J. Neuropathol. And Exper. Neurol. 2002;61:58-63.
- Smith, J.S., Alderete, B., Minn, Y., Borell, T.J., Perry, A., Mohapatra, G., et al. Loalization of
common deletion regions on 1p and 19q in human gliomas and their association with histological subtype.
Oncogene 18:4144-4152, 1999.